1. Field of the Invention
This invention relates to enzyme compositions for ingestion by a mammal having a digestive disorder which is caused by an enzyme deficiency or which, in any event, can be alleviated by enzyme supplements. More particularly, the invention relates to improved enteric coated enzyme-containing compositions for ingestion by a mammal, as well as to methods for making such a composition.
2. Description of the Prior Art
It is well documented in the literature that exogenously administered pancreatic enzymes from animal sources can remedy the enzyme deficiency caused by various diseased states of the pancreas, e.g., pancreatitis, pancreatectomy, cystic fibrosis, etc. Fewer data exist for enzymes from plant and microbial sources.
Pancreatic enzymes are active under near neutral and slightly alkaline conditions. Under gastric conditions, i.e., in the presence of acid and pepsin, most of the enzymes are irreversibly inactivated with resulting loss of biological activity. Therefore, it is imperative that the exogenously administered enzymes be protected against gastric inactivation and remain intact during their transit through the stomach into the duodenum.
While the transit of the enzymes intact through the stomach is essential, it is another requirement for maximum efficacy that the enzymes be released in the duodenum within 5 to 30 minutes, since digestion by pancreatic enzymes and absorption of the metabolites take place primarily in the upper segment of the intestine, i.e., duodenum and upper part of the jejunum.
The normal pancreas, in reponse to food stimulation, gradually releases the digestive exzymes, mostly in their inactive precursor form, into the duodenum. Some of the released zymogens (inactive precursors) are first activated by enterokinase to form active enzymes, e.g., trypsin from trypsinogen. The newly activated trypsin in turn generates more active enzymes in the duodenum by an autocatalytic mechanism. Simultaneously, the activated enzymes are thoroughly mixed with the arriving food from the stomach, and digestion ensues. This process takes place as long as food is pumped from the stomach into the duodenum.
Pancreatic enzymes have been used for the past seventy years to treat various digestive disorders. The early clinical results were variable. With time it became apparent that some of the poor clinical responses were due to gastric inactivation of the exogenously administered enzymes. A revived interest in enzyme-containing digestive aids occurred in the late 1950's and early 1960's, with the development of acid stable enteric coatings. Thus, it was believed that the detrimental effects of gastric acidity on the enzymes could be avoided by the use of such enteric coatings, and more effective enzyme therapy thus made possible. A great variety of enteric coated enzyme-containing digestive aids were marketed in this period. However, most of these products contained low levels of active enzymes, often too low to effectively treat many enzyme deficiency-related conditions. Many of these products were particularly deficient in lipase.
Moreover, the coatings generally failed to protect the enzymes against gastric inactivation or to release them in an activatable state in the duodenum. Thus, most were permeable to gastric acid and many failed to disintegrate in the duodenum under neutral conditions within a reasonable time, from the point of view of being available in proper concentration in active form at the time when food which has passed through the stomach is present in the duodenum and upper jejunum.
Because of these known defects in the coatings as well as the low levels of enzyme activities of prior art digestive enzyme-containing compositions, it has long remained a desired goal to develop a highly active enzyme-containing digestive aid composition that would prevent gastric acid and pepsin inactivation of the enzymes upon passage through the stomach, and, after transit from the stomach into the duodenum, would release the enzymes in a reproducible, i.e., predictable, manner within minutes in their biologically active state.
In a pancreatic deficient state the normal physiological conditions of digestion (i.e., gradual release of pancreatic zymogens into the duodenum, their activation by enterokinase and their even mixing with the incoming food from the stomach) in the duodenum are absent or greatly impaired. Exogenous administration of the enzymes in large tablets can aggravate the already existing abnormal physiological state because large amounts of enzymes may be released into small, concentrated areas. This in turn could result in irritation and damage to the intestinal lining. Furthermore, any asynchrony that may exist between the arrival of food and of the tablets from the stomach into the duodenum will further reduce the possibility that normal digestion can take place under this condition. A tablet can arrive in the duodenum too early or too late with respect to arrival of the food. This results in unpredictable response and poor digestion.
As can be seen from the foregoing, the desiderata for a successful, highly acceptable digestive enzyme composition, which have not heretofore been satisfactorily provided by any one product, include: (1) providing a properly enteric coated composition which enables delivery of the exogenously administered enzymes intact through the stomach into the duodenum; (2) ensuring the release of the protected enzymes, in a biologically active state, into the duodenum within minutes after the passage of the compositions from the stomach into the duodenum by providing an enteric coating which will promptly dissolve in intestinal juices, and controlling the chemical composition, physical form and size of the digestive enzyme composition to promote rapid disintegration upon dissolution of the enteric coating; and (3) recreating the physiological conditions for digestion that exist in the duodenum with a normal functioning pancreas, by (a) providing the composition in small unit size form to promote even mixing thereof with the food in the stomach so that the enzymes are gradually released into the duodenum and are uniformly dispersed throughout the food arriving from the stomach, and (b) assuring that sufficient activators such as co-lipase are present to provide for the patient maximum benefit from his own naturally produced enzymes as well as those that are administered exogenously.